Abstract This revised R01 application aims to use natural medicinal compounds (NMCs) to enhance bioactivity of synthetic bone grafts. The delivery of NMCs in synthetic bone grafts, such as calcium phosphate (CaP) scaffolds, is critical to modulate bone cell-materials interactions to improve in vivo osteogenesis and angiogenesis. Using NMCs, we propose to investigate osteoinductive, 3D-Printed (3DP) CaP bone grafts without using any growth factors (GF) or proteins towards applications in orthopedics and dentistry. However, there still exists a clinical need to innovate osteoinductive synthetic resorbable biomaterials that will promote angiogenesis, exhibiting biological properties similar to autografts. We propose to use NMCs such as curcumin from turmeric, acemannan from aloe vera, and essential nutrients such as Vitamin D3 to improve osseointegration in CaPs instead of using GFs. In our preliminary studies, we have seen promising results showing angiogenesis and enhanced osteogenesis due to the presence of NMCs. We have found that curcumin can enhance osteogenesis and angiogenesis of 3DP CaP scaffolds. From our previous work, we have also established that addition of dopants such as Mg2+, Si4+, Zn2+ and Ag+ in CaP can improve mechanical properties, enhance osteogenesis and angiogenesis while improving antimicrobial response in vivo. Combining our exciting preliminary results on NMCs and established data on dopant chemistry, we propose to demonstrate next generation of synthetic bone grafts without any GF or proteins for applications in dentistry and orthopedics, which is the premise of this application. The objective of this research is to test our central hypothesis that NMC-loaded doped CaP porous 3D Printed (3DP) scaffolds will enhance osteogenic and angiogenic properties in vivo. The rationale is that once we understand the required dose for different NMCs, their release kinetics, and the mechanism of bone cell- materials interactions modulation, the key knowledge gaps, we can design GF free synthetic bone grafts similar to autografts in clinical applications. Our long-range goal is to demonstrate clinically relevant patient matched, osteogenic and angiogenic doped CaP or CaP? polymer scaffolds with NMCs that will substitute autologous bone for repair, replacement, and augmentation in orthopedics and dentistry. To achieve our research objectives, we propose two Specific Aims. Aim 1 is focused on understanding the influence of NMCs on enhanced bioactivity of porous CaP ceramic, and ceramic-polymer composite scaffolds in vitro. Aim 2 is focused on measuring osteogenesis and angiogenesis in vivo using NMC loaded porous CaP ceramic and ceramic-polymer composite scaffolds. If successful, NMCs can also work with other materials for dental and orthopedic applications.